SUMMARY Acute respiratory tract infections are the leading cause of infectious-related mortality, the fifth-leading cause of death overall. In particular, rare unrecognized acute respiratory virus (ARV) infection outbreaks caused many human diseases of unknown etiology, particularly in less developed countries. If active ARV infection can be accurately detected and effectively vaccinated or treated with the right therapy, the outbreak can be prevented or controlled. However, current clinical assays are mainly based on PCR panels, which miss rare or highly mutated emerging ARVs and can?t distinguish high-risk infections harboring active virions from bare viral nucleic acids from previous or latent infections. Additionally, there is no FDA approved comprehensive diagnostic tool compatible with rare ARV or rare ARV subtype infection. To meet this urgent and unmet clinical challenge, we hypothesize that the isolation and analysis of viable ARV virions with high purity would provide an accurate, effective and low-cost solution for clinical applications. Captis Diagnostics has developed a new IP-pending carbon nanotube size tunable enrichment microdevice (CNT-STEM) technology that performs label-free virion capture from clinical and environmental samples. The CNT-STEM system can maintain virus viability/infectivity and has been demonstrated to identify an emerging H11N9 avian influenza virus (AIV) from swab samples of wild ducks and a new infectious bursa disease virus (IBDV) strain from turkey eyelid tissue that was previously unidentifiable by common serological and molecular methods. Furthermore, CNT-STEM captures viruses with over 90% efficiency and boosts the detection limits virus isolation by 100 times. It also increases the ratio of viral reads in next generation sequencing by more than 1,000 times. In this proposal, we propose to further optimize our proprietary CNT-STEM technology for virus isolation and coupled with high throughput sequencing to detect ARV in nasopharyngeal swab samples with high sensitivity and specificity. For Aim 1, Captis Diagnostics will optimize and validate CNT-STEM technology to develop it to a research device for ARV capture that can achieve high isolation efficiency of whole virions. Aim 2 will develop a proof-of-concept clinical assay to detect whole ARV virions by coupling efficient high throughput sequencing technology with CNT-STEM-based viable virion isolation. Successful completion of these Aims will yield a proprietary advanced technology that can isolate rare ARVs and position Captis Diagnostics to pursue clinical validation of the technology in patients of ARV infection. Phase II study will focus on clinical performance of ARV diagnosis, in which CNT-STEM-based virus isolation technology will be tested with samples from ARV infection patients to validate its clinical utility with the ultimate goal of its clinical adoption and FDA clearance.